Drug-drug interactions of simnotrelvir/ritonavir: an open-label, fixed-sequence, two-period clinical trial.

Autor:	Ye PP; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Yao BF; Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Yang Y; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Simcere Zaiming Pharmaceutical Co. Ltd., Nanjing, China., Yang XM; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Li Q; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Song LL; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Chen KG; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Zhou HY; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Shi JY; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Zhang YH; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Zhao FR; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China., Guo ZJ; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China., Xu SS; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China., Chen J; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Simcere Zaiming Pharmaceutical Co. Ltd., Nanjing, China., Goh AH; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China., Zhu SW; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China., Zheng Y; Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Zhao W; Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, China; Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: zhao4wei2@hotmail.com.
Jazyk:	angličtina
Zdroj:	Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases [Clin Microbiol Infect] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI:	10.1016/j.cmi.2024.09.007
Abstrakt:	Objectives: Simnotrelvir is a small-molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp. Hence, the drug-drug interaction potential of simnotrelvir/ritonavir should be investigated. Methods: This drug-drug interaction study was an open-label, fixed-sequence, two-period phase I clinical trial in Chinese healthy adult subjects, divided into three cohorts, including simnotrelvir/ritonavir co-administrated with a strong CYP3A and P-gp inhibitor (itraconazole) and inducer (rifampicin), and with a specific CYP3A substrate (midazolam). Results: The results demonstrated that compared with administration of simnotrelvir/ritonavir alone, the co-administration with itraconazole increased the geometric least-square mean ratio (GMR) of the expose (area under the plasma concentration-time curve from time zero to the lowest detectable plasma concentration [AUC 0-t ]) of simnotrelvir by 25% (GMR 125%, 90% CI 114-137%), whereas co-administration with rifampicin significantly decreased the AUC 0-t of simnotrelvir by 81.5% (GMR 18.5%, 90% CI 16.4-20.9%). Notably, simnotrelvir/ritonavir increased the AUC 0-t of midazolam by 16.69-fold (GMR 1769%, 90% CI 1551-2018%). The co-administration of simnotrelvir/ritonavir and rifampicin caused the increased amount and severity of treatment-emergent adverse events, especially hepatotoxicity. Discussion: The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, whereas the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam. Clinicaltrials: gov Identifier: NCT05665647. (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu